Pyruvate inhibits zinc-mediated pancreatic islet cell death and diabetes.

Abstract

AIMS/HYPOTHESIS:

We have shown that zinc ion (Zn2+) in secretory granules of pancreatic beta cells could act as a paracrine death effector in streptozotocin-induced diabetes. As Zn2+ has been reported to perturb glycolysis, we studied if pyruvate could inhibit Zn(2+)-mediated islet cell death in vitro and streptozotocin-induced diabetes in vivo by normalizing intracellular energy metabolism.

METHODS:

Cell death was measured by quantitative viable cell staining and Hoechst/propidium iodide staining. ATP was measured by bioluminescence determination. Pyruvate was infused through the tail vein 1 h before streptozotocin administration. Beta-cell volume was measured by point counting of the insulin-containing cells.

RESULTS:

Zn2+ induced classical necrosis on MIN6N8 insulinoma cells which was associated with a rapid decline of intracellular ATP levels. Pyruvate inhibited Zn(2+)-induced necrosis of insulinoma cells and depletion of intracellular ATP by Zn2+. Pyruvate did not inhibit other types of necrosis or apoptosis. Energy substrates such as oxaloacetate, alpha-ketoglutarate and succinic acid dimethylester also attenuated Zn(2+)-induced insulinoma cell death. Methylpyruvate that does not generate NAD+ in the cytoplasm or alpha-ketoisocaproate that stimulates ATP generation exclusively in mitochondria also protected insulinoma cells from Zn(2+)-induced necrosis. Pyruvate infusion inhibited the development of diabetes by protecting beta-cell mass after streptozotocin administration.

CONCLUSION/INTERPRETATION:

These results indicate that pyruvate inhibits Zn(2+)-induced necrosis of beta cells in vitro by protecting intracellular ATP levels and also streptozotocin-induced diabetes in vivo where Zn2+ has been reported to act as a paracrine death effector.

• Authors: I Chang, N Cho, J-Y Koh, M-S Lee
• Journal: Diabetologia (Diabetologia) Vol. 46 Issue 9 Pg. 1220-7 (Sep 2003) ISSN: 0012-186X [Print] Germany
• PMID: 12898018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Polyomavirus Transforming
• Antioxidants
• Tumor Necrosis Factor-alpha
• NAD
• Etoposide
• Interferon-gamma
• Pyruvic Acid
• Adenosine Triphosphate
• Staurosporine
• Zinc

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antigens, Polyomavirus Transforming
• Antioxidants (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Diabetes Mellitus, Experimental (pathology)
• Etoposide (toxicity)
• Insulinoma (pathology)
• Interferon-gamma (pharmacology)
• Islets of Langerhans (drug effects, pathology)
• NAD (metabolism)
• Necrosis
• Pancreatic Neoplasms (pathology)
• Pyruvic Acid (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Staurosporine (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Zinc (antagonists & inhibitors, pharmacology)